Methods of inhibiting gastric secretion with benzo(c)phenothiazines



United States Patent 3,505,452 METHODS OF INHIBITING GASTRIC SECRETION WITH BENZO[c]PHENOTHIAZINES Paul N. Craig, Ambler, and William G. Groves, Norristown, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Continuation-impart of application Ser. No. 593,297, Nov. 10, 1966. This application Jan. 16, 1968, Ser. No. 698,148

Int. Cl. A61k 27/00 US. Cl. 424247 5 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions having gastric antisecretory activity containing benzo[c]phenothiazines having an aminoalkyl side chain at the 7 position and a method of inhibiting gastric secretion.

This application is a continuation-in-part of copending Ser. No. 593,297, filed Nov. 10, 1966, now abandoned.

This invention relates to benzo[c]phenothiazine derivatives containing pharmaceutical compositions and the method of inhibiting gastric secretion using said compositions. More specifically this invention relates to a method of inhibiting gastric secretion with derivatives which are not anticholinergic in action and which do not possess the typical tranquilizing activity associated with phenothiazine compounds.

Prior to the present invention known compounds employed to inhibit gastric secretion have also demonstrated anticholinergic activity. The present invention has pro duced safe and effective compounds having antisecretory activity which are not anticholinergic in action and are therefore free of the concomitant mydriatic and anti salivary side effects which are common to known anticholinergics.

It has been reported that chlorpromazine inhibits gastric secretion (Am. J. Med. Sci., 230 [6]:601, 1955). Since then other phenothiazine tranquilizers have been tested for this activity. However, to date it has not been possible to develop a phenothiazine compound capable of producing significant inhibitory efiects on gastric acid secretion which has no significant effect on the central nervous system as a tranquilizer. In all cases the phenothiazines employed possessed too much central nervous system activity to be utilized as medication for excessive gastric acid secretion.

The novel pharmaceutical compositions and method of this invention are particularly advantageous in that not only do they produce significant inhibitory effects on gastric acid secretion without being anticholinergic in action, but further, at the anti-secretory doses one does not get the typical tranquilizing activity which is associated with other phenothiazines. The use of the benzo- [c]phenothiazines of this invention therefore produces a definite separation of tranquilizing and gastric antisecretory action.

For example, a representative compound of this invention was compared with chlorpromazine for central nervous system effects. The compounds compared have the following formula;

chlorpromazine 3,505,452 Patented Apr. 7, 1970 It will be noted that both phenothiazine derivatives have the same N-substituted dimethylaminopropyl side chain on the nucleus. Using the well known Confinement Motor Activity Test (J. Pharm. Sci., 53:1046-50, 1964) to determine the CNS depressant activity of the compounds it was revealed that chlorpromazine had a DD (depressant dose-50) of 6.8 mg./kg.., orally. When Compound A of the present invention was tested under the same conditions it had a DD of 666 mg./kg. or only the depressant activity of chlorpromazine.

Further and more important the above benzo[c]phenothiazines are essentially free of tranquilizing properties. When the same compounds were tested for a blockade of the conditioned escape response in rats chlorpromazine demonstrated an ED of 10.5 mg./ kg. orally. The above noted benzo[c]phenothiazine was administered in a dose as high as 250 mg./kg. It not only failed to produce an ED but also failed to produce a block of conditioned escape response in rats. The test employed is the well ac cepted CR test published by Cook and Weidley in Ann. NY. Acad. Sci., 740-752, March 1957.

Most advantageously, the compositions of this inven tion are in dosage unit form and comprise a nontoxic pharmaceutical carrier and a benzo[c]phenothiazine which has the following structural formula:

Formula I when: X represents lower alkyl, lower alkoxy, hydrogen or halogen; A represents a straight or branched alkylene chain containing up to four carbon atoms, and Z represents a basic terminal group, for example, amino, diloweralkylamino, such as dimethylamino, diethylamino or dibutylamino; mono-loweralkylamino, such as methylamino or ethylamino; or a five to seven membered heter ocyclic amino group of not more than 12 carbon atoms such as pyrrolidinyl, piperazinyl, piperidinyl, N-loweralkylpiperazinyl, N-loweralkylpiperidinyl, N-loweralkylpyrrolidinyl, N-hydroxyloweralkylpiperazinyl such as N-hydroxypropylpiperazinyl, N-alkanoyloxy-loweralkylpiperazinyl having alkanoyl groups of from 2-18 carbon atoms such as heptanoyloxyethylpiperazinyl, N-acetoxybutylpiperazinyl or N acetoxyethylpiperazinyl, N hydroxyloweralkoxy-loweralkylpiperazinyl such as N-hydroxypropoxypropylpiperazinyl or nortropinyl.

Advantageous chemical components of the compositions of this invention are represented by the above structural formula: When: X represents hydrogen, halogen or lower alkoxy; A represents a straight or branched alkylene .chain containing from two to four carbon atoms, and Z represents dimethylamino, methylamino, N-loweralkylpiperazinyl, N-loweralkylpiperidinyl or N-loweralkylpyrrolidinyl.

The preferred chemical components of these compositions are 7-(3-dimethylaminopropyl)benzo[c]phenothiazine and 7- (Z-dimethylaminoethyl) benzo [c] phenothiazme.

When the term lower alkyl is employed above, aliphatic groups having not more than four carbon atoms are indicated.

The benzo[c]phenothiazines of Formula I or a nontoxic acid addition salt thereof will be present in these pharmaceutical compositions in an amount sufficient to inhibit gastric secretion without limiting side effects. Preferably the composition will contain the benzo[c]phenothiazine ingredient in an amount of from about mg. to about 250 mg, advantageously from about 15 mg. to about 100 mg. per dosage unit.

The benzo[c]phenothiazines as illustrated in Formula I and present in these novel compositions are prepared by forming the benzo[c]phenothiazine nucleus by methods well known to the art. (I. Am. Chem. Soc., 81, 496, 1959). For example, the benzo[c]phenothiazines may be prepared by the classical method of phenothiazine formation such as thionation of properly substituted N-phenyl-B- naphthylamines in the presence of a catalyst such as iodine.

Condensation of the 7-H-benzo[c]phenothiazines with a reactive tertiary aminoalkyl ester in an inert organic solvent such as benzene, xylene, or toluene in the presence of a suitable acid binding agent yields the desired product. Any reactive tertiary aminoalkyl ester containing the desired aminoalkyl group may be used, such as the halides, preferably bromide or chloride.

Exemplary of such acid binding agents are alkali metal amides, preferably sodium, potassium or lithium amide. Other suitable acid-binding agents are alkali metal hydrides, preferably sodium hydride, or alkali metal aryl or alkyl compounds, preferably phenyl or octyl sodium.

The mono-loweralkyl amine compounds are prepared by reacting the dialkyl base with cyanogen bromide in an inert organic solvent and hydrolyzing with base to yield the desired product.

A pharmaceutically acceptable organic or inorganic acid addition salt of the base with a nontoxic salt may be used instead of the base. Preferably, the hydrochloride salt is used. However, other salts such as those derived from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as with the 8-halotheophyllines, for example 8-chlorotheophylline and 8-bromotheophylline, and like nontoxic acids may be used. Such salts are easily prepared by methods known to the art. The base is reacted with either a stoichiometric amount of the desired organic or inorganic acid in an aqueous miscible solvent, such as ethanol or acetone, with isolation of the salt by concentration and cooling or an excess of the acid in an aqueous immiscible solvent such as ethyl ether or chloroform with the desired salt separating directly.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers, are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.v Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent may include any time delay material well known to the art, such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmageutical forms can be employed. Thus, if a solid carrier is used the preparation can be t blet d. p aced in a hard g l tin ap ule n. powd 4 I or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.

The method in accordance with this invention comprises administering interally to animals in an amount sufficient to inhibit gastric secretion a compound as represented by the above Formula I or a nontoxic addition salt thereof usually combined with a pharmaceutical carrier, for example, any of the above compositions. In the well-known Brodie et a1. test for antisecretory activity in rats (Amer. J. Physiol., 2022812-814, 1962) a significant inhibition of acid output was observed when oral does of 11.2 mg./ kg. to 60 rug/kg. were administered. The benzo[c]phenothiazines preferably will be per unit of base in an amount from about 5 mg. to about 250 mg. and advantageously from about 15 mg. to about mg. The administration may be parenterally or orally, the latter being the preferable route of administration. Advantageously equal doses will be administered one to four times daily. Preferably the daily dosage will be from 5 mg. to about 1.0 g. and most advantageously from about 15 mg. to about 400 mg. When the administration described above is carried out inhibition of gastric secretion is eifectively achieved without the typical tranquilizing or depressant activity associated with phenothiazines.

These preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary or variously mixing and dissolving the ingredients as appropriate to the desired end product.

The following examples are not limiting but are illustrative of pharmaceutical preparations of this invention.

EXAMPLE 1 Twenty grams of phenyl-fi-naphthylamine and 5.2 g. of sulfur are heated in a flask to a temperature of 150 C. for approximately one and one-half hours. At the end of the heating period the mixture is distilled and the distillate is solidified and recrystallized from benzene to yield benzo[c]phenothiazine having a melting point of 178179 C.

A suspension of 7 g. of benzo[c]phenothiazine, 1.7 g. of sodamine and 5 ml. of 'y-dimethylaminopropyl chloride in 100 m1. of xylene is heated at reflux for six hours. The reaction mixture is then treated with water and the xylene layer is extracted with dilute hydrochloric acid. The acid extract is neutralized with ammonium hydroxide and extracted with benzene and the solvent was removed to yield 7- 3-dimethylaminopropyl) benzo [c] phenothiazine.

The hydrochloride salt is prepared by treating the free base with ethereal hydrogen chloride. Recrystallization from ethanol and ether yields the salt having a melting point of 199201 C.

EXAMPLE 2 benzene is heated at reflux for five hours. Water is added at the end of the reflux period and the resulting benzene layer is separated and extracted with dilute hydrochloric acid. The acid extracts are then neutralized with ammonium hydroxide. The free base is extracted with benzene and the benzene evaporated to yield 7-(2-dimethylaminoethyl)benzo[c]phenothiazine.

The free base is converted to the hydrochloride salt by reacting an alcoholic solution of the base with hydrogen chloride gas. Evaporation of the volatiles in vacuo leaves the salt having a melting point of 221-222.5 C.

EXAMPLE 4 A mixture of 6.7 g. of 7-(3-dimethylaminopropyl) benzo[c]phenothiazine (prepared as in Example 1), 1.25 g. of cyanogen bromide and 150 ml. of benzene is heated at reflux for four hours. The mixture is then extracted with acid and the benzene is removed in vacuo. The resulting nitrile is then refluxed for six hours with a 70% alcoholic solution of potassium hydroxide. The alcohol is removed and the mixture extracted with ether to yield 7- (3-methylaminopropyl) benzo [c] phenothiazine.

EXAMPLE 5 Following the procedures of Examples 1 and 2, equivalent amounts of benzo[c]phenothiazine and the following tertiary aminoalkyl esters are condensed to give the corresponding 7-tertiaryaminoalkyl benzo[c]phenothiazine:

( a) 3-bromo-l-diethylaminopropane (b) 3-chloro-2-methyl-1-dimethylaminopropane (c) 1- 3-chloropropyl) -4-methylpiperazine (d) N-methyl-Z- (Z-chloroethyl piperidine (e) N-methyl-3- (chloromethyl piperidine (f) N-methyl-3- (chloromethyl pyrrolidine (g) 2-chlorol-morpholinylethane (h) N- 3-chloropropyl piperidine (i) N- 3-chloropropyl) pyrrolidine EXAMPLE 6 A stirred mixture of 6.0 g. of benzo[c]phenothiazine (prepared as in Example 1), 1.5 g. of sodium amide and 130 ml. of xylene is refluxed for 40 minutes. A solution of 5.0 g. of 1-formyl-4-(3'-chloropropyl)piperazine in 30 ml. of xylene is added and the mixture refluxed for 12 hours. The reaction mixture is treated with about 50 ml. of water and the separated organic layer extracted with dilute hydrochloric acid. The acidic extracts are made basic with sodium carbonate solution and further extracted with benzene. Distillation of the solvent in vacuo gives the residual product l0-[3-(N-formyl piperazinyl) propyl] benzo [c] phenothiazine.

A solution of 3.5 g. of the above free base in 25 ml. of ethanol and 1.5 ml. of 40% sodium hydroxide solution is heated at reflux for two hours. The solvent is removed in vacuo and the residue treated with benzene and water. The dried organic layer is evaporated to give the product 7-(3-N-piperazinylpropyl)benzo[c]phenothiazine.

EXAMPLE 7 One equivalent of ethylene oxide is added to a mixture of 4.5 g. of 7-(3-N-piperazinylpropyl)benzo[c]phenothiazine (prepared as in Example 6) in 30 ml. of methanol and the mixture heated at reflux for two hours. The solvent is removed to give 7-[3-(N-2-hydroxyethylpiperazinyl) propyl] benzo [c] phenothiazine.

EXAMPLE 8 One equivalent of ethylene oxide is added to a mixture of 6.2 g. of 7-[3'-(N-Z-hydroxyethylpiperazinyl) propyl]benzo[c]phenothiazine (as prepared in Example 7) in 75 ml. of methanol and the mixture heated at reflux for two hours. The solvent is removed to yield 7-[3'- (N hydroxyethoxyethylpiperazinyl)propyl]benzo[c] phenothiazine.

6 EXAMPLE 9 5.0 g. of 7-[3-(N-Z-hydroxyethylpiperazinyl)propyl] benzo[c]phenothiazine (prepared as in Example 7) is dissolved in benzene and acylated with 4.0 g. of acetyl chloride in 20 ml. of benzene by refluxing for 30 minutes. The solvents are removed in vacuo to give 7-[-3-(N- acetoxyethylpiperazinyl propyl] benzo [c] phenothiazine.

ethyl)benzo[c]phenothiazine are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid and compressed into tablets.

One tablet is administered four times a day.

EXAMPLE 1 1 Ingredients: Mg. capsule 7- 3-dimethylaminoethyl) benzo [c] phenothiazine 150.00

Lactose 100.00

Screen above ingredients through a #40 mesh screen, mix well and fill into a #1 hard gelatin capsule. One capsule is administered three times daily.

EXAMPLE 12 Ingredients: M g. capsule 7-(3-dimethylamino-2-methylpropyl) benzo[c]phenothiazine 250.00 Magnesium stearate 5.00 Lactose 400.00

Screen above ingredients through a #40 mesh screen,

mix well and fill into a #0 hard gelatin capsule. One capsule is administered three times a day.

EXAMPLE 13 Ingredients: Mg./ tablet 7- [2- (N-rnethyl-Z-piperidyl) ethyl] benzo [c] phenothiazine 25.00 Calcium sulfate, dihydrate .00 Sucrose 25.00 Starch 15.00 Talc 5 .00 Stearic acid 3.00'

The sucrose, calcium sulfate and 2-(p-trifluoromethylbenzhydryloxy)ethylamine sulfate are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at 120 F. and passed through a #20 mesh screen. These granules are then mixed with the starch, talc and stearic acid, passed through a #60 mesh screen and compressed into tablets.

EXAMPLE 14 Ingredients: Mg./capsule 7-[3-(4 methylpiperazinyl)propyl]benzo[c] phenothiazine 250.00

Lactose 100.00

Screen above ingredients through a #40 mesh screen, mix well and fill into a #0 hard gelatin capsule.

7 EXAMPLE 15 Ingredients: Mg./capsule 7-[3 (N hydroxyethoxyethylpiperazinyl)- propyl]benzo[c]phenothiazine 100.00 Peanut oil 200.00

The ingredients are mixed to a thick slurry and filled into a soft gelatin capsule.

EXAMPLE 16 To a mixture of 24.9 g. of benzo[c]phenothiazine in one liter of acrylonitrile is added 1 ml. of a 40% solution of benzyltrimethylarnrnonium hydroxide, and the mixture is heated on the steam bath with stirring for two hours. After removing most of the acrylonitrile by vacuum distillation, the 7-cyanoethylbenzo[c]phenothiazine separates out, and is recrystallized from acetone.

The cyanoethyl intermediate (10 g.) is reduced in a bomb in 200 ml. methanol containing 20 g. of liquid ammonia, at 1000 lbs/in. hydrogen and 110 C. for 12 hours, using a Raney nickel catalyst. After removal of the catalyst, the volume is reduced to about 50 ml. of distillation, and excess alcoholic hydrogen chloride is added to form the amine salt. Evaporation to dryness in vacuo, followed by recrystallization from absolute ethanol and ether, yields the crystalline hydrochloride of 7- S-aminopropyl) benzo [c] phenothiazine.

We claim:

1. The method of inhibiting gastric secretion which comprises internally administering to an animal suffering from excess gastric acidity an amount sufiicient to inhibit secretion without limiting side effects of a free base or its nontoxic pharmaceutically acceptable acid addition salts, said free base having the formula:

in which:

X is a lower alkyl group having up to four carbon atoms, a lower alkoxy group having up to four carbon atoms, hydrogen or halogen;

A is an alkylene chain having up to four carbon atoms;

and i Z is di-loweralkylamino, mono-loweralkylamino, amino, pyrrolidinyl, piperidinyl, piperazinyl, nortropinyl, morpholinyl, N-loweralkylpiperazinyl, N-loweralkylpiperidinyl, N-loweralkylpyrrolidinyl, N-hydroxyloweralkylpiperazinyl, N-loweralkanoyloxy loweralkylpiperazinyl or N-hydroxyloweralkoxy loweralkylpiperazinyl.

2. The method of claim 1 in which a dosage unit of from about 5 mg. to about 250 mg. of the free base or its nontoxic pharmaceutically acceptable salt is internally administered to a mammalian organism one to four times daily.

3. The method of claim 1 in which the base is a compound in which A is an alkylene chain having from two to four carbon atoms, Z is dimethylamino, methylamino, N-methylpiperidinyl, N-methylpiperazinyl or N-methyL- pyrrolidinyl, and X is hydrogen.

4. The method of claim 1 in which the base is the compound 7-(3-dimethylarninopropyl)benzo[c]phenothjazine.

5. The method of claim 1 in which the base is the compound 7-(Z-dimethylaminoethyl)benzo[c]phenothiazine.

References Cited Shirley, J.A.C.S. 81, pp. 1496-1498 (1959).

ALBERT T. MEYERS, Primary Examiner s. 1. FRIEDMAN, Assistant Examiner 

